Disease due to infection by the human immunodeficiency virus (HIV) continues to offer unprecedented challenges to the health sciences and biology, along with equally extraordinary opportunities for original investigation and discovery. The epidemic and its consequences have profoundly and irrevocably affected all aspects of biomedical science and health-care practice, including dentistry. AIDS and HIV infection cause a wide range of serious oral lesions which we have investigated for several years. This renewal application proposes a series of integrated and multidisciplinary, yet focused and specific, studies which build on the achievements of the first four years of the Oral AIDS Center at the University of California, San Francisco. The proposal is submitted by a group of clinical, epidemiological and laboratory investigators whose coordinated research on oral manifestations of AIDS/HIV infection has been innovative and productive. It proposes new approaches in response to the changing challenges posed by the epidemic. There is need to understand the changing demographics of the epidemic; changes in the epidemiology of the oral lesions related to HIV infection; changes in the natural history of HIV infection; and the effects of continually changing therapy directed at HIV and at the consequences of HIV infection. We believe that the unique group of epidemiology cohorts and clinic populations to which we have access, plus our proven record of successful collaboration with these groups, make it highly likely that we can continue to answer important epidemiological questions, including many which have arisen during the course of the initial grant period. The two integrated molecular biological/clinical studies proposed will focus on the two commonest and most significant oral lesions of HIV infection, oral candidiasis and hairy leukoplakia. Oral candidiasis is one of the most prominent oral lesions of HIV disease, a significant indicator of CD4 numbers and a predictor of the development of AIDS. Yet there is little understanding of how Candida becomes pathogenic in the immunocompromised patient, or indeed, whether exogenous virulent strains are involved or not. We propose to explore the molecular biological basis of that pathogenicity with the ultimate goal of understanding opportunistic fungal infection in order to prevent and control it. Hairy leukoplakia (HL), caused by the Epstein-Barr virus (EBV), was first seen and is still predominantly found in HIV-infected people. We propose to explore the nature of EBV infection in HL and the relationship of the virus to the oral epithelial cell, using molecular biological and other approaches, with the goals of understanding the pathogenesis of HL and of contributing to the understanding of other EBV- related diseases. We thus propose a group of three integrated multidisciplinary studies based on the unusual, perhaps unique, opportunity presented by our group to explore the interface of oral disease, epidemiology and molecular pathology. These three coordinated components will be supported by the administrative and biostatistics core and by the clinical and laboratory core.